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PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis
Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here,...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313372/ https://www.ncbi.nlm.nih.gov/pubmed/37166997 http://dx.doi.org/10.1172/JCI155938 |
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author | Jayappa, Kallesh D. Tran, Brian Gordon, Vicki L. Morris, Christopher Saha, Shekhar Farrington, Caroline C. O’Connor, Caitlin M. Zawacki, Kaitlin P. Isaac, Krista M. Kester, Mark Bender, Timothy P. Williams, Michael E. Portell, Craig A. Weber, Michael J. Narla, Goutham |
author_facet | Jayappa, Kallesh D. Tran, Brian Gordon, Vicki L. Morris, Christopher Saha, Shekhar Farrington, Caroline C. O’Connor, Caitlin M. Zawacki, Kaitlin P. Isaac, Krista M. Kester, Mark Bender, Timothy P. Williams, Michael E. Portell, Craig A. Weber, Michael J. Narla, Goutham |
author_sort | Jayappa, Kallesh D. |
collection | PubMed |
description | Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by “switching” interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak double-knockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir. |
format | Online Article Text |
id | pubmed-10313372 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-103133722023-07-03 PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis Jayappa, Kallesh D. Tran, Brian Gordon, Vicki L. Morris, Christopher Saha, Shekhar Farrington, Caroline C. O’Connor, Caitlin M. Zawacki, Kaitlin P. Isaac, Krista M. Kester, Mark Bender, Timothy P. Williams, Michael E. Portell, Craig A. Weber, Michael J. Narla, Goutham J Clin Invest Research Article Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by “switching” interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak double-knockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir. American Society for Clinical Investigation 2023-07-03 /pmc/articles/PMC10313372/ /pubmed/37166997 http://dx.doi.org/10.1172/JCI155938 Text en © 2023 Jayappa et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Jayappa, Kallesh D. Tran, Brian Gordon, Vicki L. Morris, Christopher Saha, Shekhar Farrington, Caroline C. O’Connor, Caitlin M. Zawacki, Kaitlin P. Isaac, Krista M. Kester, Mark Bender, Timothy P. Williams, Michael E. Portell, Craig A. Weber, Michael J. Narla, Goutham PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
title | PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
title_full | PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
title_fullStr | PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
title_full_unstemmed | PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
title_short | PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis |
title_sort | pp2a modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mptp-dependent apoptosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313372/ https://www.ncbi.nlm.nih.gov/pubmed/37166997 http://dx.doi.org/10.1172/JCI155938 |
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